Abstract

Prostate cancer is driven by a combination of genetic and/or epigenetic alterations. Epigenetic alterations are frequently observed in all human cancers, yet how aberrant epigenetic signatures are established is poorly understood. Here we show that the gene encoding BAZ2A (TIP5), a factor previously implicated in epigenetic rRNA gene silencing, is overexpressed in prostate cancer and is paradoxically involved in maintaining prostate cancer cell growth, a feature specific to cancer cells. BAZ2A regulates numerous protein-coding genes and directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis. BAZ2A overexpression is tightly associated with a molecular subtype displaying a CpG island methylator phenotype (CIMP). Finally, high BAZ2A levels serve as an independent predictor of biochemical recurrence in a cohort of 7,682 individuals with prostate cancer. This work identifies a new aberrant role for the epigenetic regulator BAZ2A, which can also serve as a useful marker for metastatic potential in prostate cancer.

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Acknowledgements

We acknowledge the entire team of the German ICGC Project on Early Onset Prostate Cancer. We thank M. Lupien, C. Schmidt, D. Wuttig, O. Bogatyrova, A. Postępska-Igielska and N. Schmitt for assistance with experiments and data. This project was supported by the German Federal Ministry of Education and Science in the Program for Medical Genome Research including the EOPC project within ICGC (FKZ; 01KU1001A, 01KU1001B, 01KU1001C, 01KU1001D and 01GS0890), by Krebsforschung Schweiz (KFS; 02732-02-2011), by the Swiss National Science Foundation (SNF; 310003A-135801 and 31003A-152854), by Swiss Life, by a Müller Molecular Life Science fellowship and by Mäxi Stiftung. We acknowledge assistance provided by the Genomics and Proteomics Core Facility at the German Cancer Research Center. In particular, we acknowledge the excellent technical support of M. Schick.

Author information

Author notes

    • Lei Gu

    Present addresses: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA and Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Lei Gu
    • , Sandra C Frommel
    • , Christopher C Oakes
    •  & Ronald Simon

    These authors contributed equally to this work.

    • Guido Sauter
    • , Roland Eils
    • , Christoph Plass
    •  & Raffaella Santoro

    These authors jointly supervised this work.

Affiliations

  1. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Lei Gu
    • , Zuguang Gu
    • , Benedikt Brors
    •  & Roland Eils
  2. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Lei Gu
    • , Christopher C Oakes
    • , Constance Baer
    • , Melanie Weiss
    •  & Christoph Plass
  3. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland.

    • Sandra C Frommel
    • , Cristina Y Gerig
    • , Dominik Bär
    •  & Raffaella Santoro
  4. Molecular Life Science Program, Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland.

    • Sandra C Frommel
  5. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Ronald Simon
    • , Katharina Grupp
    •  & Guido Sauter
  6. Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.

    • Mark D Robinson
  7. Swiss Institute of Bioinformatics (SIB), University of Zurich, Zurich, Switzerland.

    • Mark D Robinson
  8. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.

    • Matthieu Schapira
  9. Unit of Cancer Genome Research, German Cancer Research Center (DKFZ) and National Center of Tumour Diseases, Heidelberg, Germany.

    • Ruprecht Kuner
    •  & Holger Sültmann
  10. Oncology Research Unit, Division of Urology, University Hospital of Zurich, Zurich, Switzerland.

    • Maurizio Provenzano
  11. Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Marie-Laure Yaspo
  12. Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.

    • Jan Korbel
  13. Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Thorsten Schlomm
  14. Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.

    • Roland Eils

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  1. ICGC Project on Early Onset Prostate Cancer

    A list of contributing members and affiliations appears in the Supplementary Note.

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Contributions

L.G., S.C.F., C.C.O., R. Simon, K.G., C.Y.G., D.B., M.P., C.B., M.W. and R.K. designed the experiments and performed experimental work. L.G., R.E., C.C.O., R. Simon, Z.G., R.K., M.D.R., M.S. and K.G. performed data analysis. R.K., G.S. and H.S. provided clinical samples or data. L.G., S.C.F., C.C.O., R. Simon, C.P., G.S., R.E. and R. Santoro prepared the manuscript and figures. M.-L.Y., B.B., J.K., T.S., G.S., R.E., H.S., C.P. and R. Santoro provided project leadership. All authors contributed to the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Guido Sauter or Roland Eils or Christoph Plass or Raffaella Santoro.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14, Supplementary Tables 2, 5 and 8–13, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Expression of epigenetic regulators in prostate tumors. Related to Figure 1a. (a) List of 709 genes associated with epigenetic regulation3. (b) Expression differences of epigenetic regulators between normal prostate and prostate tumor samples.

  2. 2.

    Supplementary Table 3

    Gene expression analysis of PC3 cells upon BAZ2A or EZH2 knockdown. Related to Figure 3. Genes upregulated or downregulated by siRNA-BAZ2A, siRNA-EZH2 or both are shown. The list of RBEPM genes is included in the list of genes upregulated by BAZ2A or EZH2 depletion.

  3. 3.

    Supplementary Table 4

    Gene expression analysis of RWPE1 cells upon BAZ2A or EZH2 knockdown. Related to Figure 3. Genes upregulated or downregulated by siRNA-BAZ2A, siRNA-EZH2 or both are shown.

  4. 4.

    Supplementary Table 6

    Genes regulated in both PC3 and RWPE1 cells upon BAZ2A or EZH2 knockdown. Related to Figure 3.

  5. 5.

    Supplementary Table 7

    List of differentially methylated genes in BAZ2A-high versus BAZ2A-low tumors. Related to Figure 5.

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DOI

https://doi.org/10.1038/ng.3165

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